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Cancers 2015, 7(4), 2330-2351;

Aberrant GLI1 Activation in DNA Damage Response, Carcinogenesis and Chemoresistance

Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, 1660 Springhill Avenue, Mobile, AL 36604, USA
Department of Dermatology, University of Alabama at Birmingham, 1530 3rd Avenue South, Birmingham, AL 35294, USA
Author to whom correspondence should be addressed.
Academic Editor: Hui-Wen Lo
Received: 27 August 2015 / Revised: 12 November 2015 / Accepted: 20 November 2015 / Published: 27 November 2015
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The canonical hedgehog (HH) pathway is a multicomponent signaling cascade (HH, protein patched homolog 1 (PTCH1), smoothened (SMO)) that plays a pivotal role during embryonic development through activation of downstream effector molecules, namely glioma-associated oncogene homolog 1 (GLI1), GLI2 and GLI3. Activation of GLIs must be tightly regulated as they modulate target genes which control tissue patterning, stem cell maintenance, and differentiation during development. However, dysregulation or mutations in HH signaling leads to genomic instability (GI) and various cancers, for example, germline mutation in PTCH1 lead to Gorlin syndrome, a condition where patients develop numerous basal cell carcinomas and rarely rhabdomyosarcoma (RMS). Activating mutations in SMO have also been recognized in sporadic cases of medulloblastoma and SMO is overexpressed in many other cancers. Recently, studies in several human cancers have shown that GLI1 expression is independent from HH ligand and canonical intracellular signaling through PTCH and SMO. In fact, this aberrantly regulated GLI1 has been linked to several non-canonical oncogenic growth signals such as Kirsten rat sarcoma viral oncogene homolog (KRAS), avian myelocytomatosis virus oncogene cellular homolog (C-MYC), transforming growth factor β (TGFβ), wingless-type MMTV integration site family (WNT) and β-catenin. Recent studies from our lab and other independent studies demonstrate that aberrantly expressed GLI1 influences the integrity of several DNA damage response and repair signals, and if altered, these networks can contribute to GI and impact tumor response to chemo- and radiation therapies. Furthermore, the ineffectiveness of SMO inhibitors in clinical studies argues for the development of GLI1-specific inhibitors in order to develop effective therapeutic modalities to treat these tumors. In this review, we focus on summarizing current understanding of the molecular, biochemical and cellular basis for aberrant GLI1 expression and discuss GLI1-mediated HH signaling on DNA damage responses, carcinogenesis and chemoresistance. View Full-Text
Keywords: hedgehog signaling; GLI1; DNA damage; carcinogenesis; chemoresistance hedgehog signaling; GLI1; DNA damage; carcinogenesis; chemoresistance

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Palle, K.; Mani, C.; Tripathi, K.; Athar, M. Aberrant GLI1 Activation in DNA Damage Response, Carcinogenesis and Chemoresistance. Cancers 2015, 7, 2330-2351.

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